PROJECT SUMMARY The lung is a richly innervated organ. Strong evidence, including recent findings from us, demonstrates that neuronal control plays central roles in basic lung response to the environment, including immune activity, as well as airway and vascular smooth muscle tone which impacts air conductance and pulmonary blood pressure, respectively. However, the full extent of how the nervous system affects lung function remains unclear, and little is known of the anatomical and molecular features of the neurons that innervate the lung. Here, we propose to use cutting-edge viral-based circuit tracing, single cell transcriptomic and haploid ES cell- based genome editing technologies to: 1) label lung-innervating neurons; 2) determine their localization and projection pattern; 3) generate knockin mouse lines that will lay the foundation for neuromodulation of lung function. Findings generated in mice will be tested in human biopsy samples to delineate conserved versus species-specific mechanisms. With the development of wireless, implantable devices, neuromodulatory therapy is on the horizon. Findings from this study will lay the necessary foundation for precise manipulation of organ function through the nervous system, and thus closely comply with the mission of the SPARC program.